4-oxa prostaglandin f &#39; -type compounds

ABSTRACT

This invention is a ground of 3-and 4-oxa PG-type compounds, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including antiulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement at term, and wound healing.

United States Patent 1191 [451 Nov. 18, 1975 Nelson [54] 4-OXA PROSTAGLANDIN F a-TYPE COMPOUNDS [75 Inventor: Norman A. Nelson, Galesburg,

Mich.

[73] Assignee: The Upjohn Company, Kalamazoo.

Mich.

[22] Filed: Apr. 17, 1974 [21] Appl. No.: 461,583

Related 0.8. Application Data [63] Continuation of Ser. No.- 332.067. .Feb.- 13,-l973. abandoned,' which is a continuation-in-part of Ser. No. 47.169. June 17.. I970 abandoned.

[30] Foreign Application Priority Data July 29. l969 United Kingdom; 38073/69 June l5. I970 United Kingdom l60488/70 June 16. I970 United Kingdom 4099/70 June [8. I970 Australia l6530/70 July 29. 1970 Belgium .9217? July 28, l9 70 Denmark 39l7/ 70 July 28. l970 France 70.27783 July 23. 1970 Germany 2036471 [56] References Cited FOREIGN PATENTS OR APPLICATIONS 2,036,47l l2/l97l Germany 260/468 Primary Examiner-Robert Gerstl Anomey, Agent. or Firm-Morris L. Nielsen [57] ABSTRACT This invention is a ground of 3-and 4-oxa PG-type compounds, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including antiulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement at term. and wound healing.

70 Claims, No Drawings A systematic name for 4-oxA PROSTACLANDlN-Fd-TYPE COMPOUNDS CROSSTREFERENCE TO RELATED APPLlCATlONS This'application is a continuation of my copending application SeriNo. 332,067, filed Feb. l3,- I973, now abandoned, which was a continuation-in-part of my then copendingapplication Sen-No. 47,l 69, filed June 17, 1970, now abandoned.

BACKGROUND OF THE INVENTION This'invention relatesto compositions of matter, and to' methods and; intermediatesfor producing-them. ln

1 particular, the seyer'al "aspects 'of this invention relate to novel analogs of some of the known prostaglandin's, for

example, prostaglandin E, (PGE,), pro'staglandin E, G HL :Progiaglandin l iiiv an PFGI f)- 2" '.)'v w ws r'ostaglandin A (PG sponding'"PG' s, and the dihydro PG, derivatives, to

- novel methods for' producing those novel prostaglandin' A5); prostaglana :din Bfj (PfiBrlliprostagla'ndin (PO8 the corre- Q analogs, and td-n'o elchemical intermediates useful-in Each ot-the 'abo ef mentione'd known prostaglandins ing structure and atom numbering:

25 V l is a derivative of prostano'ic acid which has the follow PGB, has the following structure:

\,COOH

Each of the known prostaglandins PGE,. PGF PGF; PGAg, 'and P08, has a structure the same as that -s own for the: corresponding PG, compound cxcept that in each. C-5 and G6 are linked with a cis carhon-carbon double bond. For example, PG E: has the following structure:

Each of the known .PG, prostaglandins has a structure the same-as that of the PG, compounds except that in each,.C-l7and C-l8 are linked with a cis carbon- .carbon double bond. Forexamplc, PGE has the following structure:

' coon Vlll v w Each dihydro derivative of PGE,, PGF PGF,

PGA and P68, has a structure the same as that sh wn forlthe-corresponding PG compound except that in each; G1 3 and 014 are'linked with a carbon-carbon single bdnd .j For example, dihydro-PGE, has the fol- Ql wingstr-ucture:

prostaglandin-formulas mentioned above each I haveseveral centers of asymmetry. As drawn, formulas llto lX each repre'sentsfthe particular optically active form of'the prostaglandin obtained from certain mammalian tissuesfl'foreita'mpleQsheet vesicular glands,

swine lung. and human seminal plasma. or by reduction or dehydration of a'prostaglandin so obtained. See, for example. Bergstromet'al Pharmacol. rev.'20. (i968). andreferences cited thcrelm- 'l'he mirror image of each lformula'represents. a molecule of the-enantiomer of that prostaglandin.i'l1e.racemic form ofthe prostaglandin consists of equal numbers of=twotypes of mole- 'cules, one represented by oneof-the above fonnulas and the other represented by the mirror image of that formula. Thus, both formulas are needed to define a ratanev ring'indicate substituents in alpha configuration;

i.e. below the plane of the :cyclopentane ring. Heavy SOllCl line attachments to the cyclopentane ring indicate substituents in beta configuration. i.e.. above the plane 1 of the cyclopentane ring.

Prostaglandins with' -carboxyl-terminated side chains attached to the cyclop enta'ne ring in beta configuration are also ltnowmThese are derivatives of 8-iso-prostanoie acid which has the following formula:

' coon For example. these compounds, and especially the PGE compounds. are useful in mammals. including man. as nasal decongestants. For this purpose. the compounds are used in a dose range of about it) pg. to about l0 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray. both for topical application.

The POE. POP, PGF and PGA compounds are useful in the treatment of asthma. For example. these 3 compounds are useful as bronchodilators or as inhibitors of mediators, such as SRS-A. and histamine which are released from cells activated by an antigen-anti- .body complex. Thus. these compounds control spasm in alpha (8) configuration. See Nature 212. 38 (1966) for discussion of the stereochemistry of the prostaglanll'lS.

PGE,. PGE,. dihydro-PGE and the corresponding PG F.. PGF,, PGA', and; PCB compounds. and their. esters. acylates. andf fiphannacologieally acceptable salts; are 'extremely'potent in"cau sing various biological responses-For that reason. these compounds are useful for phurmoc'ologi'cal'purposes. See. forexample. Berg-g strom et al.. pharmacOIQ'RevQZOQl (1 968 and referand facilitate breathing inconditions such as bronchial asthma. bronchitis. bronchiectasis. pneumonia and emphysema. For these purposes. these eompounds are administered in a variety of dosage forms. e.g.. orally in the form of tablets. capsules. or liquids; rectally in the fennel suppositories; parenterally..subcutaneously. or 'intramuscularly. with intravenous administration being preferred in emergency situations. by inhalation in the form of aerosols or solutions for nebulizers; or by insuffiation inthc form of powder. Doses in the range of about 0.0l to 5 mg. per kg. of body weight are used I to '4 times a day. the exact dose depending on the age. weight. and-condition of the patient and on the frequency and route of administration. For the above use these prostaglandins can be combined advantageously with other anti-asthmatic agents, such as sympathomimetics (isoproterenol. phenylephrine. ephedrine. etc. xanthine derivatives (theophylline and aminophylline and corticosteroids (ACTH and predinisolone). regarding use of these compounds see South African Pat.

ences cited 'thereinLA'fewof those biological responses are systemic blood pressure lowering in" the case of the PGE and PGA compounds as'm'easured. for?example.'

in anesthetized T(pentobarbital sodium) pentoliniurritreatedirats with. indwelling aortic-andright heart can-,-

nulas; stimulation of ,s moothmusclefas; showmfor e'xample.*by te'sts on' 'stripsof guinea pig ileumfrabbit d'u v odenum. or gerbil colonypotentiation of other smooth muscle stimulants; antilipolytieiactivity as shown by antagonism of epinephrine-induced. mobilization of free .4 fatty acids. .or-inh ibition1of the spontaneous release of 1 glycerol fro'r n isolatedratfat pads; ihhibition of gastric secretion in the ofthe PGE and PGA compounds as shown indogs withs'ecre'tion 'stimulated'by food o r histamine infusion;- activity o'nthe central nervous systern; controlling jspasmgand; facilitatinglbreathing" in asthmatic conditions; decreasing blood platelet; adhe siveness as shown by platelet to glass adhesivene'ss gandinhibition j ofblood platelet aggregation and-thrombus 7 formation induced by various physical stirnuli eigg artcrial injury. and {various 'bioehemical -f'stimuli. e.g.. ADP.'ATP. sertatonimthrombin. and collagen; and in the case of the PGE'. a'nd PGB compounds.-- s'tirnula tion of epidermal proliferationand 'lteratinization --asfs hown when applied in culture'=- :'to embryonic chick and rat skin segments v The PCB and PGAcompounds are useful in mammals. including man andcertain useful animals. e.g., dogsand pigs. to reduce-and control excessive gastric secretion. thereby'reducing or avoiding gastrointestinal ulcerformation. 'and accelerating the healing of such ulcers already present in the gastrointestinal tract. For this purpose, the compounds'are injected or infused intravenously. subcutaneously; or intramuscularly in an infusion dose range about 0.=l pg. to "about 500 pg. per kg. of body weight per minute." or in a total daily dose by injection'or infusion in jthe range about 0.1 to about 20 mg. per kg. of body weight per day. the exact dose 7 depending on the age. weight, and condition of the patient or animal. and on the frequency and route of administration.

The PGEQPGFQ and PGF j compounds are useful whenever it is desired to inhibit platelet aggregation. to reduce the adhesive character of platelets, and to remove or prevent the formationof thrombi in mammals. including man.- rabbits, and rats. For example. these compounds are useful in the treatment and prevention of myocardial infarets.lto treat and prevent post-operative thrombosis. to promote patency of vascular grafts following surgery. and to treat'conditions such as atherosclerosis. arteriosclerosis. blood'clotting defects due Because of.these fbiologicalresponses.;these ltnown V prostaglandins' m useful to study. prevent. control. oralleviate a wide variety "of: I diseases and; undesirable physiological conditions inbirds'andmammals. includto lipemia. and other clinical conditions in which the underlying etiology is associated with lipid imbalance or. hyperlipidemia. For these purposes. these compounds are administered systemically. e.g.. intraveing humans. useful domestic animals. pets. and zoologi 'nou'sly. subcutaneously. intramuscularly. and in the 5 form of sterile implants for prolonged action. For rapid -response. especially in emergency situations. the intravenous route of administration is preferred. Doses in the range about 0.005 to about 20 mg. per kg. of body reason. these compounds are useful to promote and ac- The PGE and P68 compounds promote and acceler ate the growthoflepiderm'al cellsfand' keratin in ani-.'

mals, including humans, useful domestic animals,"'pets;

zoological specimens. and laboratory animals. For that.

celer ate' healing of skiniwhich has been damaged. for

example. by burns..wounds'.' and abrasions. and after surgery. These-compounds are also usefulto promote Some of the novel prostaglandin analogs of this inand accelerate adherence and growth of skin"'aut0- vention have a smaller or greater number of carbon g P y= P' (Davis) gr f which 'ato'ms than the formulas shown above. in cither the earn d PL skinlesrsi ma h! mqw Outward bony-terminated side chain or the alkyl-t'erminated side growth rather than initially. and to .retard-rejeetion of i homograftsu- For'example. fi e of the novel Prostaglandin analogs P' 'PQ i h p f Preferably" of this invention are represented by the formulas: administered topically-at or near the cute where-cell growth and keratinformation is desired. .advanta! geously as-an' aerosol liquid "or ,mieronized powder spray, as anisotonie aqueous solution in'the case of wet dressingsgorf'as' a lotion; cream, or oint'ment in combi-- nation with the usual pharmaeeuticallj acceptable dilu- 3 ents. In some instances; for example. when there issubstantial fluidloss asL in the case of extensive burn's or skin loss due to other'jc'aus'es, systemic administration is 5 advantageous.- for example, by intravenous injection'or V infusion, separateor-in combination with the usual'in- 1 fusions of blood,'plasma; or substitutesfthere'of;Alternative routes of administration are subcutaneous or; in-' J' 1 I tr'amus'cular near'the'siteIoral;subligital, buc'ealirectaly or vaginal; 'l'he'fc'xact dose dependsflongsuchfaetors iasi the 'routepf.administration{,andjthefagcgweight and condition 1 of; th e'-subjeet. ;-To 1 illustrate a" wet dressing for topical applicationjto second andIor-thirdflegr'ee 1i 1 burns of skin reafi to 25;s quare centimeters would ad vantageo'usly involve 'use'of an isotonie'aqueous solu tion containing l-toSQO#gJmhofthePGBlcompound"3 or several. times that;eoncentratioitij'of th'PGE coin; pound. Especially fortopical u'se, theseprostagl andins are usefulin eornbina'tion witiiantibiotiesgffofleitainpleii; gentnmyein.neomyeiii'gpolyrnyxin B,-baeitracin;.,Spec-' tinomyein. and oxytetraeicline;'withotherahtibacteri als. for example; 'mafnide' hydrochloride, sulfadiazine; furazolium chloride.;an'd"nitrofurazone,"andfwith corticoid steroids, for: example. hydtoeortisorie preglitis'cy; lone. methylprednisolone. arid flupi'ednis'olone, each'o a those t'xsing used in th'e cfombinatio "the ualfcon centra'tion suitablefo'r' its'useffalone' v "SUMMARYOETHE INVENTION lt isapui'pose hisj inventionftofProiride 'noyel 3-oxa and 4 oxa'prosta'l ridin'analogsi' for makingtliem;

Xlll

XVI

The-novel' prostaglandin analogsjof th H g I each Yi b y l (I Q .i "in place ofth'e; methylene" -s- (CHg-f-fimoietyia'tt positioti1or at.the,. 4#positions r of the prostanoic'acid'f r'niula 1 450: example. 3 93?: POE one of the novel compounds'of this invention is represented-.bythe formula: 1

XVll

Based on its relationship toPGE and prostanoic acid.

'I' the-compound of formula xlll isnamed 3-oxa-4-nor- PGE the compound of formula XIV is named 4-0xa- 4a.4b-dihomo-'l3.l4-dihydro-lS-beta-PGF the compound of formula XV is named 3-oxa-l9.20-dinor- PGA the compound of fonnula XVI is named lt-(ciaxa-f t m d b 5,6-deh dro-20-methyl-PGBn and the compoun o m ggzfii f .formula xvlljs named'3-oxa-4a-hom0-PGF ration fo rl POE-{,itdbe iaggu qy1 v lhefolloWing formulas represent the novel 'Ji n -M my These names for the compounds of formulas Xlll to XVll are typical of the names used hereinafter for the 'carboxy terminated chain and eight carbon atomsin the hydroxy-containing chain. In these names, 3-oxa" and 4 oxa indicatea'n, oxa oxygen (OJ-in place of the 3-methylene;and 4 methylene. respectively of the v PG compound.

The use of fnor" or fdinor"'in the namesfor the novel compounds of thisinvention indicates the absence oi one or two of the chain carbon atoms and the attached hydrogen atoms. The number ornumbers in front of nor, -or dinor'indicate which of the original,"

'prostanoic acid carbon atoms are missing inthe named A The use 'oifhomoi or ifdihomo as in'the names ofthe formula-XlVja'ndI-XVll' examplesindicate. one or two additional carbon atoms in thecarboxy-terminated Y 'l side chain. In the name of,.the formula -XlV example 1" 4a,'4b-dihomo indicates two additional carbon atoms specifically between the oxygen atom at;4'.and. the C-5 carbon atom. There are; therefore, eight carbon at oms and oneoxygeni'atom inf that side chain 'ins'tead of the six carbon atoms and one oxygen atom of the nonnal 3-oxa. structure of this invention.

ln the name of" the ro aula-xvr'exa e. "2b:

nietliyl'f-indicates' tl'lat a methyl groupsre'pla'ce's a hydrogen on C-20.The 'rnethyl-tenninated cha'inof that examplethereforelhz ts nine carbon atoms, ..;Where therei's-branching or'fluoro sub stitutionjjn the sidejchains, the poinitsofattachment t'othe side-chains are indicated in' the conventionalfmanner. following the? atomic numbering of theprostanoic acid skeleton (l). Novel compounds or this invention withjepiiconfiguv ration' 'for, 1 thehydroxyf at C- 1 5 I are s o'f designatedby 51 i ,using ISAbeta'I in 'thefnamfe; An-j ex'ani'pleis'jthejfname given above forthecompoundoflformula. XIVL' lf .li5

beta does notappear intheInarneQthe natura icpnfigm;

ration for the C- l 5. hydroxy, identified as theS configu- 1 4 -oS a compounds iofth is invention in the same'gopti-f cally active fonnasthe'naturally. occuring prostagla XXXVI I n XLI XXXIX 15 PGF type. Formulas XXXVIII to XLVII represent 3-oxa and 4-oxa compounds of the PGA type. Formulas XLVIII to LVlI represent 3-oxa and 4-oxa compounds of the P68 type.

In formulas XVIII to LVII, ,r, is hydrogen. alkyl of one to l2=carbon atoms,inelusive, cycloalkyl of 3 to 10 carbonatoms.' inclusive;' aralltyl of 7 to I2 carbon atoms. inclusive, 'phenyl. phenyl substituted with one to 3 chloro or alkyl of one'to 4 carbon atoms; inclusive. or ethyl substituted in the B-positionwith 3 chloro. 2 or 3 bromo. or I; 2, or 3 iodo. R, is alkyl of one to 10 carbon atoms. inclusive. substituted with zero to 3 fluoro. Q is I B; oui

wherein R is hydrogen or'alkyl of one 10 carbon atoms. inelusiveiil is alkyl of one to 4'carbon atoms. inclusive. substituted with zero. one. 2. or 3 'fluoro. R R. R and R. are hydrogen or alkyl of one to 4 carbon with respect to the G5 to C-6 double bond in the carboxyl-terminated side chain. In all of the compounds containing the C -to-C double bond. that double bond is in trans configuration, and the chain containing that moiety is attached to the cyclopentane rirt'g'in beta configuration in compounds encompassed by formulas XVIII to XLVII.

. The novel 3-oxa and 4-oxa compounds of this invention include raeemic compounds and both optically active enantiomeric formsthereoflAs discussed hereinabove. two structural-formulas are required to define accurately these racemic compounds. The formulas" as drawn herein are intended to represent compounds I with the same configuration as the naturally-occurring I prostaglandins. However, for convenience in the charts form but also the racemic compoundswhich generally undergo the same-reactions.

a; 'Formula XVIII represents 3-ox a-PGEI Iformula XI hereinabove) when Cili is- -(CH,) Q is atoms, incIusiverThe divalent moiety C,'.H represents alkylen'e, of one. to l0 carbon*atoms.,.inclusive. with one; to 5 ,*j: earbon' atoms, in clusi jve.;;"-between CH,- and" O- The? divalent imoietyi C il -e representsalkylene of one to 9icarbon 'atoms, inclusive. with 1; one to carbon atoms; inclusive; ijbetween represents 'alkyle neo'fone to'j8'carbon atomsginclusivey ail-+1representsi'alltyleneof'onejjtofl'carbotifatoms; in-

figuration.

Formulas xvm-m mu aL vjn wa the asa'm= isomerswherein Q is either;

or I

ethyl propyl, butyl, andisomericforms thereof. Examples. of alkylj-of-onei to 8 carbon atoms; inclusive, are

those given above-and pentyl,"he xyl', heptyl, octyl, and

isomeric fonnsth'ereof. Examples of alkylof one to I2 f. atoms, inclusiye; are those given above, and no- 'nyl, 'de'cyl, undecyl'g dodecyl "and isomeric forms itltereof. Examplesio'f cycloalkyl of 3 to I O..earbon iatoms, inclusive. which includes alkyI-substituted cy- '"cyclobutyl}'2,34;triethyleyclobutyl, cyclopentyl, 2.2- 1 dimethylcyelopentyl, B-pentyIcycIQpentyL'3-tert-butylcyclopentyl. cyclohexyl; gi-tert-butylcyclohexyl, 3-isopropyleyclohexyl; j2.2-dimethylcyclohexyl, cyeloheptyl, cyclooctyl. cyelononyl. and cyclo'deeyl. Examples of,aralkyl of Ho I2 carbon atoms, inclusive, are benzyl phenethyl 'l-phenylethyla 2-phenylpr'opyl, 4-

ph'enylbutyl;i3-phenylbutyl; Z-(l-naphthylethyl), and I Y I-(Z-nziphthylmethyl)ifEttamples of phenyl substituted 50. a inclusive,* ,are p-ehlorophenyl;im ehlorophenyl, o-

by one to"3 chloro or alkylfof one to 4 carbon atoms,

chlorophenyl, 2,4-dichlorophenylp 2,4;6-trichlorophei.e., where the'hydroxyl-is,in ieitherflalphaf(natural) on f 1 betav configuration.=. ReferringiJto the lip'rostano icd atomnumbe'ring (formuIasIIaboi/ekthe pointofatta'ch- I p H a merit corresponds"td Cflfii t'and.,herein,regardless of- Qyflttoroisoheptyl, 8'-fluor oo ctyl. 3.4- r yl.-

the variation in the C-"l to C-7 carboxy chaimthese'epimers are referredftoas C I5 epimers' Formulas xxvm through xxxvu wherein the Q9 phenyl.-,2.5 dimethylphenyl, 4,-chloro-2-n1ethylphenyl,

'difiuoropentyl; '5,5-difluorop'entyl, 5 .5.5-triflu oropentyl, and.l0.l0,lO-trit'luorcidecyl. I

Examples of alltyleneiwithin the various scopes of C,Hg, C,',.H,,,,, C,.I7l,',,, C,,H,',, and CqHqg as'those are de- 65 fined above, are methylene 'ethylene, trimethylene, tetramethylene. pentamethylene and those alkylene with one or more alkyl substituents on one or more carbon atoms(alkyl groupsljasbranching? IAfseven'ratom- 'carboxylfltenninated ch'ai is'ino 17 -CH(CH2CH:) CH: CH(CH:) O -CH(CH- The novel formula XVlll-XXVll POE-type 3-'oxa and 4-oxa compounds, the novel formula XXVlll-XXXVII PGF -type and PGF -typc 3-oxa and 4-oxa'come pounds, the novel formulaXXXVllI-XLYII P GA- type 3-oxa and 4-oxa compounds, and the novel formula XLVlll-LVll PGB-type 3-oxa and 4-oxa compounds, andtheir racemic forms, each cause the biological responses described above for the ROE, POP. PGFp, PGA, and R68 compounds, respectively, and each of these novel compounds is accordingly useful for the above-described'corresponding'purpose's, and is usedfor thosepurposes in the same manner as described above.

Theknown oe, Porn, orn, 'PGA, and P08 compounds uniformly cause multiple biological re.-

tivity; Moreover, formany. applications, these known.

- prostaglandinshave anj inconveniently short duration of biological, activity. lnstriking contrast, thenovel for-' mula XVlll-to-LVII analogs and their'racemic forms are substantially more .specificwith regard to potency in causingprostaglandin-like biological responses, and

' have a substantially longer duration of biological activ-' ity. 'l'herefore,eaeh of these novel-prostaglandin analegs is useful finpla'ce of one of the corresponding, abovemntioned known prostaglandins for at least-one- 'of the pharmacological purposes indicated above; for the lat ter, and issurprisinglyjand unexpectedlywmore useful-ifor thatpurpose' because'it'has a differentiand" narrower spectrum" a of biological) activity manque t I known'prosta'glandin, and therefore is more specific in used to attain the'desiredlresult; r

preferred. For example, it is preferred that the cat-bottyterminated chain in each formula contain achain of six atoms between,thec'arboxylfand'the cyclopentane ring. Oneofthose' six 'atorn'sfwill the 'orta atom'and 4 l the other five-will be carbon" atoms.- Accordingly. and with reference to'formulas XVlllt'o iA/ll, it is preferred atx' s u-:- P 1- .'h foroptimum absorption of the compound by the body that -C,,,l- I,,,, representa-i-Z-carbOnIIdivaIent; chain,

These preferences do' li not' exclude eluded :injthe compoundsfof form las": XXlJQxXXlIL-T.

xxvu','- xxxt, xxxm, xxxvu; xu, .xun, XLVII, LI, LIII,.and LVII, i.e.". formulas wherein.

the carboxy terminated,side chain ls"'-4'- oxaandcontains a'carbbn carbon double or triple bond.,ln' each of these compounds, the q of -C,H 'is.at' leastone, and at least ,seven' atoms," one' oxygen] (oxa) and six carbons, are present between thecarboxyl and pr ferredforprolo'nge the cyclopentane ring. In these compounds, the preference is for that minimum chain, i.e., q is one. Another preference for the compounds of formulas XVlll to LV" is that R R r R and R, be hydrogen or methyl-All of those R groups can'be hydrogen, all can be methyl, or there can be any of the possible combinationsof hydrogen and methyl, It is especially preferred for prolonged duration of biological activity that both R, and R be methyl, and/or that R, be methyl.

' Certain variations in the nature of R in formulas XVHFXXV. XXVlll-XXXV. XXXVlIl-XLV. and XLVlll. LV are especiallyimponant. in the known prostaglandins, e.g., POE. the portion of the molecule corresponding to R, in the above-mentioned formulas is pentyl. It is preferred that R, be pentyl in formulas XVlll-XXV,-XXVlll XXXV, XXXVll XLV, and XLVlll-LV. lt-isalso preferred that R, be straight chain alkyl of 3 to 7 carbon atoms, inclusive, with or a without a fluoro substituent at the l-position e.g..

g is one to 5. Alternately, R, is represented by wherein R, is hydrogen or fluoro and g is one, 2, 3, or 5. Pentyl and l-fluoropentylare, of course, included in this preference,

In compounds offormulas XXVI, XXVll, XXXV l.

XXXV", XLV], XLVILLVl, and LVII, it is preferred that C 11,, be methylene and that R, be ethyl.

Another advantage of the novel compounds of this inventiomcspecially the preferred compounds defined 'hereinabove, compared with the known prostaglandins. is that-these novel compoundsare administered effectively orally, sublingually, intravaginally, buccally, or

rectally, in additionto usualintravenous, intramuscular, or subcutaneous injection or infusion methods india r l cated above for the uses of the known prostaglandins. 1R5 activ ty andcauses smaller and fewer undesrred stde l effectsthanithelcnown: prosta'glandin. Moreove'n because of its prolonged activity, fewer'and'smaller doses of the novel. prostagla'ndin analog; can frequently 1 be 1 These qualities are advantageous because they facilivtate maintaining uniform levels of these compounds in the body yvithfewerg shorter, or smaller doses, and makepossible.self-administration by the patient.

5 The -P..GE,.. P.GF,. PGFs, P A, n R y 3-oxa and '4-oxa compounds encompassedby formulas XVlll-ito LVll including the special classes of compounds described above, are used for the purposes described above in the free acid form, in ester form. or in phannacologically acceptable salt fonn. When the ester form is-us'ed-thelestenjs any of those within the above definition of R '..Howeve'r, it is preferred that the esterbe alkylof one to IZ carbon' atoms, inclusive. of .th ose alkyl, rnethylfand ethyl are especially preferred *or-"experi'mentalanimal system; .and straight-chain oct'y l, nonyl,, decyl', unde'cyl, and dode'cyl are especially Y V l e activity in the body or experirhentalfanimalg-k Pharmacologically acceptable salts of these formula .XVlll to LVll compounds useful for the purposes described above are those with phannacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.

"Especially preferred metal cations are those derived from the alkali metals, e.g., lithium. sodium and potassium,'and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other The 3-oxa and 4-oxa PGE, PGF PGFp, PGA, and PGB type compounds encompassed by formulas XVlll to LV" are produced by the reactions and procedures described and exemplified hereinafter.

The various 3-oxa and 4-oxa PGF -type and PGF -type compounds encompassed by formulas XXVIIl-XXXVIl are preparedby carbonyl reduction of the corresponding PGE type compounds encompassed by formulas XVIII-XXV. For example, carbonyl reduction of 3-oxa PGB, gives a mixture of m PGF and 3-oxa PGF These ring carbonyl reductions are carried out by methods known in the art for ring carbonyl reductions line, l-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-

dimethylpiperazine, Z-methylpiperidine, and the like, as well as amines containing water-solubilizingor hydrophilic groups, e.g., mono-, di-, and triethanolamine, cthyldiethanolamine, n-butylethanolamine, Z-amino-lbutanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2- methyl- 1 -propanol, tris-( hydroxymethyl )aminomethane, N-phenylethanolamine, N-(p-tert-amylphenyl)- diethanolamine, galactamine, N-methylglucamine, nmethylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the like.

Examples of suitable pharmacoiogically acceptablev quaternary ammonium cations are tetramethylammonium, tetraethylammoniurn, *benzyltrimethylammonium, phenyltriethyla'mmonium, and the like.

of known prostanoic acid derivatives. See, for example, Bergstromet al., Arkiv Kemi l9, 563 (1963), Acta Chem. Scand. 16, 969 (1962), and British Specification No. 1,097,533. Any reducing agent is used which does-not reactwith carbon-carbon double bonds or ester groups. preferred reagents are lithium(tri-tertand PGB type compounds encompassed by formulas XVlll ,to LVll-including-gjthe special-classes of compounds described above, are also used-for the purposes described above in free hydroxy form or -in the form wherein the hydroxy moieties are transformed to lower butoxy)aluminum hydride, the metal borohydrides, es-

pecially sodium, potassium and zinc borohydrides, and metal trialkoxy borohydrides, e.g., sodium trimethoxyborohydride. The mixtures of alpha and beta hydroxy reduction products are separated into the individual alpha and beta isomers by methods known in the art for the, separation of analogous pairs of known isomeric prostanoic acid derivatives. See, for example, Bergstrom et al., cited above, Granstrom et al., J. Biol. Chem. 240, 57 (1965), and Green et al., J. Lipid Research 5, 117 (1964). Expecially preferred as separation methods are partition chromatographic procedures, both normal and reversed phase, preparative thin layer chromatography, countercurrent distribution procedures, and column chromatography.

The various ii-oxa and 4-oxa PGA-type compounds encompassed by formulas XXXVlll-XLVll are prepared by acidic dehydration of the corresponding PGE type compounds encompassed by formulas .XVllL XXYllQ, For example, acidic dehydration of 3-oxa PGE, gives 3 -oxa PGA These acidic dehydrations are carried out by methods known inthe .art for acidic dehydrations of known prostanoic acidderivatives. See, for example, pike et compounds are used as free acids, as esters, and in salt form all as described above. H a

As discussed above, the, compounds of formulas XVlll to LV" are administered in various ways for various purposes; e.g., intravenously, intramuscularly, subcutaneously, orally, intravaginally, rectally, buccally,

sublingually, topically, andin. theform of sterile im plants for prolongedaction. For intravenous injection or infusion, sterile aqueous, isotonic solutionsare preferred. For that purpose, it is preferred because ofincreased water solubility'that R, ,inthe fomiula XVI]!- to-LVll compound be hydrogen-or a pharmacologically' acceptable cation. For subcutaneous'or intramuscular injection, sterile solutions or suspensionsof-the-acid, salt, or ester form in aqueous or non#aqueous rnediaare used. Tablets, capsules; and liquid preparations such'as syrups, elixirs, and simplesolutions, with the'usual pharmaceutical carriers are" used for oral sublingual administration. For rectal or vaginal administration, suppositories prepared as known in the art are used-For tissue implants, a sterile tablet or silicone rubber capsule or other object containingor impregnated with the substance is used.

al., Proc. nobel Symposium ll, Stockholm (1966), Interscience Publishers, new York, pp. 162-63 (1967); and .British Specification No. 1,097,533. Alkanoic acids of 2. to 6 carbon atoms, inclusive, especially acetic acid, are preferred acids for this acidic dehydra- 56 tion Diluteaqueous solutions of mineral acids, e.g., hy-

drochloric. acid, especially in the presence of a solubilizing diluent, e.g., tetrahydrofuran, are also useful as reagents for this acidic dehydration, although these reagents may cause partial hydrolysis of an ester reactant.

various. 3oxa and 4-oxa PGB-type-compounds encompassedgby formulas XLVll-lVll are prepared by basic dehydration of the corresponding POE type compoundsencompassed by formulas XVlII-XXVII, or

by'c'ontatihg the corresponding PGA compounds encompassed "by. formulas vXXXVlIl-XLVII with a base. For example, both B oxa PGE, and 3-oxa PGA give B-oxa PGB, on treatment with base.

These basic dehydrations and double bond migrations are carried out by methods known in the art for similar reactions of known prostanoic acid derivatives.v

See, for example, Bergstrom et al., J. Biol. Chem. "238,355 (1963). The base is any whose aqueous solu- -'tion has pH greater than l0. preferred bases are the alkali metal hydroxides. A mixture of water and sufficient of a water-miscible alkanol to give a homogeneous reaction mixture is suitable as a reaction medium. The PGE-type or PGA-type compound is maintained in such a reaction medium until no further PfiB type compound is formed, as shown by the characteristic ultraviolet light absorption near 278 nm for the PCB type compound.

The various transformations of 3 oxa and '4-oxa PGE type compoundsjof formulas XVIII to XXV to the corresponding 3-oxa and 4-oxa RGF... POP PGA,.

and PCB type compounds are. shown in'Chart A; wherein Q,R R and are asdefined above, and wherein A is --CH,--CH, or trans-CH=CH, Q is cHAar A aCH -V-COOR A-C-R: ll HO Q acid "acu -v-cooa base .ll carbonyl Q reduction hose 2 -V-COOR ,cH v-cooa CR5RQ, or -C I CC H O-CR -,R5CR1- Rg, WhCl'Clll R5, R5, R1, Ra, CnHzm CYII ZUIJ C,l-l,,, and C l-l are as defined above, with the proviso that V is C,.H,..O-CR,R-.- or -C,,.- Hun-O-CRgRg-Clhkuwhen A is -CHz- CH, The 3-oxa and 4-oxa PGE, type compounds of formulas XXVI and XXVI] are transformed to the corresponding 3-oxa and 4-oxa PGF a, PGF PGA and PGB 'compounds by analogous reactions.

The various 3-oxa and 4-oxa dihydr o-PGE dihydro- PGF dihydro-PGF dihydro-PGA. and dihydro- PGB, type compounds encompassed by formulas XXIV, XXV. XXXIV, XXXV, XLIV, XLV, LIV, and LV are prepared by carbon-carbon double bond reduction of the corresponding PGE, PGF... PGFb. PGA, and PGB type compound containing a trans double bond in the hydroxy-containing side chain. A cis or trans doubled bond or an acetylenic bond can also be present in the carboxy-terminated side chain of the unsaturated reactant, and will be reduced at the same timeto -CH=CH For example, dihydro-S-oxa-PGE, is produced by reduction of 3-oxa-PGE, 3-oxa-PGE,, or 5 .6-dehydro- 3-oxa-PGE,.

These reductions are carried out by reacting the unsaturated PGE, PGF PGF PGA. or PGB type compound with diimide, following the general procedure described by van Tamelen et al., J. Am. Chem.

-Soc., 83, 726 (1961). See also Fieser et al., Topics in 'OrganicfChemistry," reinhold Publishing Corp., new 40 York, pp. 432-34 (1963) and references cited herein.

The unsaturated acid or ester reactant is mixed with a salt of azodifonnic acid, preferably an alkali metal salt such asthe disodium or dipotassium salt, in the presence of an inert diluent, preferably a lower alkanol such as methanol or ethanol, and preferably in the absence of substantial amounts of water. At least one molecular equivalent of the azodiforrnic acid salt is used for each multiple bond equivalent of the unsaturated reactant. The resulting suspension is then stirred, preferably with exclusionflof oxygen, and the mixture is made acid, advantageously with a carboxylic acid such as acetic acid; When a reactant wherein R is hydrogen is used; that carboxylie acid reactant also serves to acidify an equivalent amount of the azodiforrnic acid salt. A reaction temperature inthe range about 10 to abou't'40 C. is usually suitable. Within that temperature range, the reaction is. usually complete within less than 24 hours. The desired dihydro product is then isolated by conventional methods, for example. evaporation of the diluent, followed by separation from inorganic materials by solvent extraction.

In the case of the 3,-oxa and 4-oxa unsaturated PGE. PGF and PGF type reactants, the reductions to the corresponding 3-oxa and 4-oxa dihydro-PGE,, dihydro-PFG and dihydro-PGF, compounds are also carried out by catalytic hydro enation. For that purpose, palladium catalysts, expecially on a carbon carrier, are preferred. It is also preferred that the hyaction mixture by conventional methods, for example.

removal of the catalyst by filtration or centrifugation. followed by evaporation of the solvent.

Diimide reductions and catalytic hydrogenations to produce the various novel 3-oxa and 4-oxa dihydro compounds of this invention from the corresponding 3-oxa and 4-oxa PGE,, PGF PGF, PGA|..and PGB, type compounds are shown in ChartB, wherein Q,R .R,. and"- are as defined above, and W is -C,.H-

whereinC H C H RQR R- and-R are as defined above.

CHART a diimide or hydrogen catalyst ,,CH,-W-(.0OR,

u \C-R,

diimide. Q

2 cm-w-coon.

cmcm-fi-n,

cH,-w-cooR.

/H /c-c\ I H fl-a,

Q [diimide r 2 :CH,WCOOR.

These diimide reductions and catalytic hydrogenations to produce'the same novel 3-oxa and 4-oxa-dihydro compounds of this invention from the corresponding 3-oxa and 4-oxa PGE;, PCP. PGF2B, P-GA and PGBgtypecompounds and also from the corresponding compounds with a trans-ethylenic or an acetylenic linkage in place of the cis-ethylenic linkage in the earboxyl-terminated side chain. are shown in Chart C, wherein Q. R1, Rban d are as defined above, U is cis-CH-CH-, tran's"--CH-CH'-, or. C C-, and Y is -C,,H;, -O -CR.R. or -C H -O CR R -CR1R. wherein P. q, R,-,, R6, R and R8 are as defined above.

v- The 3-oxa' and 4oxa compounds of the PGE PGF, PGF Q, PGA,, and PCB, type wherein the carbon-carbon double bond in the carboxy-terminated side chainis in cis-configuration' are prepared by reduction'of the corresponding acetylenic 3-oxa and 4-oxa compounds. i.e'.', those with a carbon-carbon triple bondin place of said carbon-carbon double bond. For

' that purpose. there are used any of the known reducing ence of pyridine. See Fieser etal, Reagents for Organic Synthesis," pp. 566-67. John Wiley &=Sons. lnc.. New York. NY. (1967). These reductions are shown in Chart D, wherein Q. R Rh and are as defined above, and Y is -C,H,,,-O- CR,R.- or -C,,l-l- OCR,R. CR R,.. These 3-oxa and 4-oxa cis compounds of the PGE,. PGF PGF, PGA,, and

P08, type are also prepared as described hereinafter.

CHART E CH; YCOOR LVlll -c H C-Jl, u

cll,-c c-Y-coolz. ux

I H OHH c-c I H/ f-R,

The 3-oxa and 4-oxa PGE type compounds of formulas XVIII to XXIII except wherein 'R is hydrogen, and. the 3-oxa and 4-oxa PGA type compounds of formulas XXXVlll to XLlll except wherein Ryis hydrogen are p prepared by the series of reactions shown in Chart E, 40 RHOSO 0503 wherein 0, R and V areas defined above, R and R are alkyl of one to 4 carbon atoms, inclusive Ri is the same asthe above definition of R except that R does not include hydrogen, R isalkyl of one to 5 carbon o r atoms, lncluslve, and lndlcates exo or endo configu- .cl-l,-v-cooR.. ration with respect to the moiety attached to the cyclo- XI! LXI propane ring;

The 3-oxa and 4 oxa POE, type compoundsof formulas XVIII and XIX. the 3 oxa and v4-oxa 5,6-dehydro-PGE, type compounds of formulas XXII' and 5 H6 E XXIII, the 3-oxa and 4'-ox'a PGA typecompounds of I formulas XXXVIII. and XXXIX, and the 3-o ta' and '1 4-oxa 5,6-dehydrd-PGA, typecompoun'dsjof formulas XLII and XLlll are alsopreparedby thesen'es of reac- Q tions shown in Chart 'F, 'wherein Q, R R R and R are as defined above, Z is +0.1 -0- sRn CmHm -0 CRs s 1R| I CpHQp -0 -CR3R. 01' "\CqHjq" O-ClhR. -CR1R.-, andindicates exc -or endo configuration with respect to-the moiety attached to E the cyclopropane ring:

It should be observed regarding the series of reactions shown in Charts E and F, that the reaction starting with glycol LX in Chart E are similar to the reactions starting with glycol LXVll in chm F. The only differences here are the definitions of the divalent moieties (Chart E) andZ (Chart F).V includes saturated, cis and trans ethylenic,' and acetylenic divalent moieties; 2 is limited to the saturated and acetylenic divalentmoi eties encompassed by V. H

' ,cm-v-coom.

LXIII LXIV I 1 no oso,R.,

' In other words. final 3-oxa and 4-oxa PGE type compounds of formuIaLXlI (Chart-E) encompass compounds of formulas XVIII to XXIII. Final 3-oxa and 4-oxa PGA type compounds of formula LXIII (Chart E) encompass compounds of formulas XXXVIII to XLIII. On the other hand, final 3-oxa and 4-oxa PGE type compounds of formula LXIX (Chart F) encompass only compounds of formulas XVIII, XIX, XXII, and XXIII. and final 3-oxa and 4-oxa PGA type compounds of formula LXX (Chart F) encompass only compounds of formulas XXXVIII, XXXIX. LXll, and XLIII.

I As will subsequently appear. an acetylenic intermediate of formula LIX, formula LX; or fonnula LXVll is transformed by reduction to the corresponding cis or trans ethylenic intermediates of formulasLlX or LX, and an ace'tylenic intermediate of formulas LIX, LX, or LXVII, or a cis or transethylenic intermediate of formulas LlXfor LX is transformed by reduction to the a corresponding saturated intermediate of formulas LIX,

LX, or LXVII.

:The initial bicycloJcetone reactant of formula LXV in Chart F is also used as an initial reactant to produce the initial bicycloketonecyclic ketalreactant of formula LVIII in Chart E. The reactions of Chart G will product cyclic ketal LVIII. Therein THP is tetrahydropyranyl, and'd ,v is phenyl.

The bicyclo-ketone reactant ofiform'ulaLXV exists in four isomeric forms.' exo ;and endo with respect to -5 theatt'achment of the C I*l:CI-I.-R, molety, and cis "andtranswithrespectto th'ejdoublebond in that moimy; Eachxif thoseisornersseparately orvarious mixtures thereof are used: as reactants according to this in- .vention to'ploducc substantially CHART o LXXll s. /H P-C R' via several ltepl Lxv cH-cn-R,

. QHFC HR1 of bicyclo-ltetone LXVJ These orthe samefinal3 1oxa on4-oxa PGEor PGA typeprods h o d= i s R: H1-. l and R2 20 CH=-Br, areknown in than or can be prepared by uct mixture. a

Theprocess for preparing either theexo or endo con figurationof the forrnula- LXV bicyclo-ketone is 30,905,,page -3 i3; ,Mar.'=,l 2.- 968; See @West Gerrnany' offenlegungssehrift' No.l ,93 7.-9 l- Zlreprintedin Farm.- Y doc Complete specifications'g'Book No; I4\,NYOH.' 68 69 R. Week R'gl iMar. 18'; 970.59;

In said Belgian-Pat na 7 02.477; a reaction'seque'nce capableot' forming 'exol ketone LXV isas 'fo llo'wsgThe dro, fi- -cyc onf'smsn l Tl E d I for ex m with fa tetr'ahydropyranyl group. Then a diazojaceti'e acid ester is 'added to] the double" bond otfgivefanyeitoj endo mixture of 'afbicyclqBQ l .om ians 's'ubsti tuted jat? 3 with'th'e protectedhydroxyjl'and at6jtvitha esterifie'df carb'oityl: The" exo e'ndofrr'iixture"isytreated-withja base-f to isomerize the endois'omer ingt he' mixture tomore of. f thefexo iso'rn er. ;Next;.the 'e'arboitylate'f'stergroup at" 6? is transformed toa'n aldehydei group. %-CHo. T en;- 1 saidaldehyde group isftransfo'rmed bythewittig reacfl tio'n, in this case to a moietyfof thejfor'mula "-CH CH-R, which 'is in exo configuration relative to the 1 a moved to regenerate theflll-hydroxy' whichis then oiti-l.-

dized. fore tample,-{by the {Jones reagent, i.e..-chromic Separation of cis asa reactantin thenext process step:

The process d scribed 702.4775 producing the e'xo form; of.'.= bicyelo-ke tone LXV uses, intermediate; thejexol of}! bicycle [3. 1 mm xa'ne'fsubstituted' at I 3 ,1 with '8 -;pro'teeted hy-v droxyieg'i; rtetrahydropyranyloity andat 6" withan escessin said orfeiiiegiifigsschiia 19091937912' leads to the ends r m ar bicyelo ke'ton e LXVgThat ei' d o'm a coecii, LXXIV LXXIII CH;;( CH;) cFflCH cl-l ch as described in Alifl phatic jFluorinecompoun'ds, A'.M. lovelace et al., YAm; 'ChemJSoc. MonographSeries 19 58, Reinhold PUbl.-Corp.;'lhose halides not available are prepared acid (seegl.LCitem; Soc; 9I-( l94' l it to'give said'e to 1 p g g a a gg; Fple'. For those 'lhalides offthe formula ai-cu -uai LXV is described'in-said"BelgianfPattfNo?702; 4717;; Howevefl asmentioned {aboVe'iithatseparatidn isusually not necessaryisineel the cisgtrans rn ittture is useful 1 i said, almpa No. a

Compound LXXIV is prepared by reacting endo-bicyclo[3. l .OI-hexane-3-ol-6-carboxylic acid methyl ester which is then reached with dihydropyan in the presence of a catalytic amount of POCI, to give the desired compound. This is then used as described in said Offenegungssch'rift No. 1,937,912 topro'duct the endo form of bicyelo-ketone LXV.

' As for exo LXV, the above process produces a mixf 'ture'of endo-cis and endo-trans compounds. These are ffs'eparatedm described for the separation of exo-cis and v a exo-trans LXV,'- but this separation is usually not necessary since. as mentioned above, the cis-trans mixtureis useful as a reactant in the next process step. In the process of said Belgian patent and said Offenlegungsschrift, certain organic halides. e.'g.. chlorides and bromides. are necessary to prepare the Wittig reagents used to generate the: generic moiety,

methods known in them." a v v o illustrate-the availability of these organic chloi'idesconsider first the above-described 3-.oxa and ta'n'e,'-o ctane. and -de'cane; and the monohalofluorohy- "drocarbons, 'e.g., CHQFCI, CH FCH BrfCHF CH Cl,

1 methods known'in the art-by reacting the cone-- or any of the other halogenating' agents useful for this --.purpose.- I t, Available alcohols j include CH CH(CF;)CHOH, (CH CHCH CH-,OH.

for exam- ;wherein'i-lal is chloro'or bromo R; is Rl-|(CHg)q, being one. 2,",'oi' -4,'-'and Rf. being isobutyl, tert-butyl, 3,3-

- t'yl; the..intermediate alcohols are preparedas follows.

".jj ln thejcase of Rii being isoboy'tylortert-butyl, known alcohols;are'converted -to' bromides. thence-to: nitriles 5fi withsodiumcyanide, thence to the corresponding carboitylie acids by hydrolysis, andthence to the correspondin'g primary alcohols by reduction, e.g.'with lithiumaluminum-hydride thus extending" the carbon .-"ehai n one carbonf atom atatimeuntil all primary alcoholsarepre paredfl -s y ,i-,lnthe ease of R being,3.3'difluorobutyl, the necessaryaleohols areprepared'from keto carboxylic acids Of the formula, CHf-CQ (CH, )}COOH, wherein r.

" is 2, 4. or 6. All of those acids are known. The methyl esters are'prepared and reacted with sulfurtetrafluoride to produce the corresponding Cl-i CF,(CH

- COOCH= compounds, which are then reduced with lithium aluminum hydride toICH Fz-(CH2)rCH- 0H. These alcohols are then transfonned to the bromideor chloride by reaction with PBr, or PCl In the case of R being' 4,4-difluorobutyl, the initial and endo or exo, and whether a cis or a trans hydroxylreactants are the known dicarboxylic acids, .HOO- ation'reagent is used. These various glycol mixtures can C--(CH,),COOH', wherein f is 3, 4, 6, or 7. These 'be separated'into individual isomers by silica gel chrodicurboxylic acids are esterifred to CH=OOC (CH,. 'matography. However, this separation is usually not ),-COOCH; and then half-saponiiied.'for example necessary. since all isomers of a particular glycol arc with barium hydroxide, to give HOOC-(CHQ equall useful as intermediates according to this inven- ),COOCH5. The free carboxyl group. is transformed tion and the processes outlined in Chart E to produce first tothe acid chloride with thionyl chloride and then fin l Pl' C f f rmulas LXI] and LXI". and then. to an aldehyde by the Rosenmund reduction. Reaction w cco ing t Chart A. n D to Product h other of the aldehydewith sulfur tetrafluoride thenlgives 1%| producfts of this imenltion.I Lxx ii h cur tcun coocn, which-b successive treatment e um ormation sy I M e cyclic wit i hi aluminum hydride i p5,, or per, git/c; ketal of formula Lvlll (Chart E) is carried out by relhc nccqsary bromide; or chloride. CHE-(CPL. acting laid glycol Wllh ti dialkyl kl0l1 0f the formula ),-CH,Br or CHF -(CH,) CH,Cl.

In the case of R being 4,4,4-trifluorobutyl'. .alde- I hydes of the formula CH OOC(CH CHQ are prev (f pared as described above. Reduction of the aldehyde R i \CvihbbsCodiuE I borohydride gives the alcohol.

e r I nk g ;gg ziggg f wherein R and R are alkyl of one to 4 carbon atoms. sponding' halocarboxylie acid which reaction with i P the R ofan i catalyst for sulfur firm-memev gives the necessary p e potassium btsulfate or 70% aqueous perchlonc H C t H acid. A large excess of the ketone and the absence of i ggz -g f gg zggpfzg t water isdesirablefor this reaction. Examples of suit- 321L723 and-J. Chem 27' 9 2 able dialkylketones are-acetone. methyl ethyl ketone.

As mentioned above," formula XVlll-to-LVll, .comdmhyikemmI-mmhflpmpyikeionetand the like g-"P t i e s"? g te s t iiiieii igftiii iifi 2,322 fi ivm i. ifig s fifi 1 .53g? transformed to cyclic ketal LlX by alkylating with an I 0 alkylation agent of the formula Hal-CH V-COOR 2221f arisiesimemzr'3.2:: aria. d v am. II; Ple ifli-oxa-lofluoro PGE" The f rmula-LXV bic chlofimt r iodincr S m cloket ones neeessa to t oduce those meiienuei'echari'p-olefinllxv isl-t-rani'fomed to qlefin Lxvl by I com u P I b 7 alkylatingiwith'an alkylationagentofthe formula Hal- 5 are a 9 impale as CH 'Z-CQOR 'Wherein R... Z,.and'Hal are as defined either of the above mentroned bicyclo-aldehydes, exoaboveI Y Y j v I .or endo withaWittig"reagent prepared from Cl-h e I y of the alkylatron p rocedures known in the art to I (CHWCQCHrB' and 'r-T l?? be useful for alkylatin'g' cyclic tt'et es with alkyl halides y s p ls-thereby transformed to v and h aloalkanoieesters are used for the transformations of LVlll to LIX and LXV to LXVI. See. for examfi ple. the 'abovementionedBelgian Pat. no. 702,477 for H- "Ih- I- e procedures useful here and used there to carry out similar alkylation's. e.g.. employing the bicyclo enamines. The resulting unsaturated ketone is reduced to the cor- For l' t it is P bc responding I 4 bromoor lodo. Any of the usual alkylauon bases. e.g

- alkali metal alkoxides. alkali metal-amides, and'alkali OH 7 metal 'hydrides, are usefulfor this alkylation. Alkali I: c metal alko'xides are preferred, especially tert-alkoxides. '-e .H,- H(CH:l| a' So'diudm-andpotassiumare preferred alkali metals. Es- I I, -peeially'preferredispotassiunttert-butoxide. Preferred w y 5 I T j =';dil u' 'ents forthisalkylation.are'tetrahydrofuran and 1.2- compoundy-Thg n group is pf qmimfn fldiinethoxyethane; outefwis'e. procedures for producing fluoro by known me thods; for'exam'ple. direetlybyresi ndq a ihs" h -d i e aand LXVI action with 2-chloro l.l .l trifluorotriethylamineior'inmandate hlEmF ki et-the a direetly. for example, by' njsformi'j" ehy'droxy. i lhese alkyla'tib n-proeeduis produce mixtures of to's'yloxy or mesyloxy, and reaeting the-resultin'gjeo' alpha and bejta'alkylationi products,.i.e; a mixture of the pound with'anhydrous'potassium fluoride iii diethy formula l lxj products' wherein';:the '96: V I COORiQE-rhoietyf."jiifhttached in: alph'afl configura- The transformation of.bicyclo-ketone olefinlsxv tdb tionglwithxcorresponding' compounds having that g y LXXI" i 'carried out byireacting olefin LXl/f moietyattached i'n 'betdeontiguration. or a mixwith a hydroxylation reagent..l-lydroxylation reagents; ture' of the formula-LXVI products with correand procedures for thispurpose are known in the art. bonding compound; having the -CH, -Z See, for example. Gunst'one. Advances inorganic COOR fmoiety in'the' beta configuration- When Chemistry. Vol. I, pp. 103-47. lnterseience Publishers.-' b t ne equiyalent of base per equivalent of New York. 0) E pecially u ef l hydroxylformula LXV'orLVllllketone is used. the alpha configation reagents for'this purpose are osmium tetrXide uration usually predominates. Use of an excess of base and performic a i (formic c P1118 hy r g n Pfl and longer reaction times usually result in production w Various isomeric s y m Obtained p se of. larger amounts of beta products. These alphabeta on such factors as whether olefin LXV is'cis'ortrans im e mi s are se arated at this stage or at any a 35. subsequent stage'in the multi-stepprocesses shown in Charts E and F. Silica gel chromatographyis preferred for this separation.

The necessary all yla ting-"a'gents' for the above described alkylations,fli.e ',fcompounds of the formulas Hal ACH, {V -QOQRQJ: and ii-lal eC l-l; --Z 'v COOR B, are prepared by methods knownin the'art. There are eightf groups of compounds encompassed by these two genera. of alkylating agents. Alkylating agents of the fonnula Hal- CH,-Z-'- -COOR{ include compounds of thefollowing formulas:

R HulCH,-C,.H g-i-COOM,

formulas LXXV'. LXXVLLXXVH, and LXXVIII; and 'also compoundsgof the following formulas:

These alkylating agents .of formulas LXXV .to

LXXXll are accessible to of ordinary skill .'in;the.,

art. For'example", the.3-oxa alkylatinfiiggsrkts of are a las LXXViLXXVIIiQXXIXJhd s tageously 'prepared by reacting-an alpha-hydroxy ester or acid of the{amulet-1090mm#300111;- I

of the formula BrCR -,R COOR,, wherein R R and R, are as defined above, is reacted in the presence of a similar strong base with a compound of the formula I i! 2II C CCPH1P OH,. .or J-CH;-CH=CH -C,,H,, -Ol-l. When both'R, and R. in the ester are alkyl, it is preferred to use the hydroxy acid or ester route. When there are two alkyl groups in Cm or C l-l on the carbon to which -OH or -G is attached, it is preferred to use the bromo acid or ester route. When a formula LXXV. LXXVll. LXXIX. or LXXX alkylating agent is desired wherein both R, and R; are alkyl and C,,H,,,'-or C,,H,,,has two alkyl groups attached to the carbon to which -Ois attached, it is preferred that .G be mesyloity or tosyloxy, or that the Br of the bromo acid or ester be replaced with mesyloxy or tosyloxy, whereupon bases and reaction conditions known in the art may be'used, for example, potassium terobutoxide in dimethyl sulfoxide. Alternatively, this group of. tetraalkyl compounds is advantageously prepared by"'using the hydroxyacid or ester route with a compound wherein G is chloro, or by using the bromo acid or ester route wherein the bromo is replaced with chloro, using freshlyjprecipitated wet magnesium hydroxide in'an inert'solvent suspension as the base. Alternativelythis group of .tetraalkyl compounds is advantageously prepared by the hydroxy acid or ester route-wherein G is iodo, and silver oxide is used as the base. Anyof these alternative routes is',;of course, userq r'nul Xvr'LX alternative procedure generally applicable to the ful't'o make the other compounds within the scope of LXXI X, and LXXX.

production of the alkylatingagents of formulas LXXV, LXXVll, LXXIX; and LXXX comprises reacting a compound of'ithe" formula 'J*-CH, -C..H=,.-OH, J -CH; C -OH,OI' J ,CH1 '-CH= Cl-i-c l-lg -ol-lwith' an ethylene oxide of the formula CHr- R R it wherein R, and R. are as defined above, in the presence 9 of an acid catalyst," "e.g'.,' hydrochloric acid, sulfuric acid, or boron trifluoride. The alcohol which is usually the" major! protuct, i.e., J-CH,-C,,H,,,-O CR,,. f Re Cl 10". J -CHg -C I CCp Hzp -O--CR5- J R -E-Cl-hOI-I, orcis ,or trans J Cl l,CH=CH-C,,H- 51- 0 CR ';R. -CH Ol i, is isolated, oxidized to the f correspondingcarboxylicacid with Jones reagent, and

thefacid esterified (R 5); 7 p .v 111i'e f,4'-oxa alkylating'fa'gents of formulas LXXVI,

LXXYIII, LXXXIQand LXXXII are advantageously prepared as described above forthe 3 -oxa compounds,

combining compounds of the formula J-'-CH',-.-CmH- 'Cnl-li, and C H are as'defined above, 'J is chlorio, I bromo, hide, or a group' transformable, to .oneof those, for example, ,-tetrahydropyranyloxyl;ori mesy- I Rs e "and alternatives described above for the preparation of loxy, and 3,v is chloro, '5 bromo, iioddfl mesy y. 1 or the like, in" the presence .gof a' strong" base, for example, sodium hydride when R,'is a carbon-con the 3 oxa"alkylating agents are applicable to the preparation of these 4-o7ta alkylating agents.

. ified to the corresponding formulas LXX V -toLXXXll 37 'lhe alkylating agents of formulas LXXV to LXXXll are esters. When an alpha orbeta hydroxy acid orv bromo acid is used as areactantas deseribed'above. the resulting product is a carboxylic acid. This acid is esteralkylating agentby known kprocedures. As will be described; hereinafter, thefester'm'oiety. R,', is chosen according to the desired type of final'3eox'aor 4-oxa prostaglandin-like product. p

.The alpha-hydrox'y. alpha-halo; beta-hydroxy, and beta-halo acids and'esters Landthe ethylene and trimethylene oxides used as described above to produce the formula LXXV to LXXXII alkylating agents'are all known in the art or are readily accessible through known methods to'those of ordinary skill in'the'rart.

s'- I CsHiP 'OHQ- T v and the-corresponding reactants with'halogen, mesyloxy 'or tosyloxy in place of;-"OH also are known'in through known methods to those of ordinary skill in" t e art.

For example, consider the compounds 25 I rnr-o-cu -o-wu to give the glycols no-cn i-on.

which are transformed by known methods to the above tetrahydropyranylethers.These ethers are also trans-,

formed by known methods to above defined.- Consider the. compounds wherein THP is as above defined, and the free valences are attached to hydrogen or to alkyl. with a total of 'zero 65 to 8 attached alkyl carbon atoms. Said compounds are, within the scope of] -CH, -C.H,.-0l-l as above defined, and are advantageously prepared by known methods from beta-hydroxyesters of the formula the art-or are readily accessible compounds within above defined.

l HO-CH -(IL-COOR wherein R is methyl or ethyl and the free valences are attached to hydrogen or to alkyl. Said esters are available through methods known in the art. e.g., the Reformatsky reaction. Said compounds are also transformed by known methods to THP-O-CH -li-Jf-BP.

compounds-within the scope of J -CH, C,H -G

' as abovedefined.

Consider the compounds wherein THP isas defined above and the free valences are attached to hydrogen or to alkyl, with a total of zero to 7 attached alkyl carbon atoms. Said compounds are within the scope of J-CH C,,H,,,-OH as above defined, and are advantageously prepared by known methods from the knownsuccinic acid half esters of the formula wherein R}, is methyljor ethyl. the carboxyl end being transformedito'THP Q-Cl-i and then the -COOR,

' end being transformed to both by known methods. Said compounds are also transformed by known methods to rur-o-cm-o-cl JJ-Br. I

the scope of J-CH -C,,H,,,-G as Consider the compounds THP-o-cH,-+-o%-%-d|-oi1 wherein THP is as defined above and the free valences are attached to hydrogen or to alkyl. with a total of zero to 6 attached alkyl carbon atoms. Said compounds are within 'the scope of J-CHrCJ-I OH as above defined. and are advant methods from ageously prepared by known 

1. AN OPTICALLY ACTIVE COMPOUND OF THE FORMULA:
 2. A racemic compound according to claim
 1. 3. An optically active compound according to claim
 1. 4. A compound according to claim 3 wherein CnH2n is straight chain alkylene of one to 5 carbon atoms, inclusive.
 5. A compound according to claim 4 wherein CnH2n is trimethylene.
 6. A compound according to claim 5 wherein R5 and R6 are hydrogen or methyl, being the same or different.
 7. A compound according to claim 6 wherein R5 and R6 are hydrogen.
 8. A compound according to claim 7 whrein R2 is pentyl.
 9. A compound according to claim 8 wherein Q is
 10. A compound according to claim 8 wherein Q is
 11. A compound according to claim 10 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, including the pharmacologically acceptable salts thereof when R1 is hydrogen.
 12. A compound according to claim 11 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive.
 13. A compound according to claim 12 wherein R1 is hydrogen, methyl, or ethyl.
 14. 4-Oxa-PGF1 , a compound according to claim
 13. 15. 4-Oxa-PGF1 , methyl ester, a compound according to claim
 13. 16. 15 -Methyl-4-oxa-PGF1 , a compound according to claim
 13. 17. 15-Methyl-4-oxa-PGF1 , methyl ester, a compound according to claim
 13. 18. An optically active compound of the formula:
 19. A racemic compound according to claim
 18. 20. An optically active compound according to claim
 18. 21. A compound according to claim 20 wherein CnH2n is straight chain alkylene of one to 5 carbon atoms, inclusive.
 22. A compound according to claim 21 wherein CnH2n is trimethylene.
 23. A compound according to claim 22 wherein R5 and R6 are hydrogen or methyl, being the same or different.
 24. A compound according to claim 23 wherein R5 and R6 are hydrogen.
 25. A compound according to claim 24 wherein R2 is pentyl.
 26. A compound according to claim 25 wherein Q is
 27. A compound according to claim 25 wherein Q is
 28. A compound according to claim 27 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, including the pharmalogically acceptable salts thereof when R1 is hydrogen.
 29. A compound according to claim 28 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive.
 30. A compound according to claim 29 wherein R1 is hydrogen methyl, or ethyl.
 31. A compound according to claim 30 wherein the C-5 to C-6 double bond in the carboxyl-terminated side chain is in the cis configuration.
 32. 4-Oxa-PGF2 , a compound according to claim
 31. 33. 4-Oxa-PGF2 , methyl ester, a compound according to claim
 31. 34. 15-Methyl-4-oxa-PGF2 , a compound according to claim
 31. 35. 15-Methyl-4-oxa-PGF2 , methyl ester, a compound according to claim
 31. 36. An optically active compound of the formula:
 37. A racemic compound according to claim
 36. 38. An optically active compound according to claim
 36. 39. A compound according to claim 38 wherein CnH2n is straight chain alkylene of one to 5 carbon atoms, inclusive.
 40. A compound according to claim 39 wherein CnH2n is trimethylene.
 41. a compound according to claim 40 wherein R5 and R6 are hydrogen or methyl, being the same or different.
 42. A compound according to claim 41 wherein R5 aNd R6 are hydrogen.
 43. A compound according to claim 42 wherein R2 is pentyl.
 44. A compound according to claim 43 wherein Q is
 45. A compound according to claim 43 wherein Q is
 46. A compound according to claim 45 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, including the pharmacologically acceptable salts thereof wherein R1 is hydrogen.
 47. A compound according to claim 46 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive.
 48. A compound according to claim 47 wherein R1 is hydrogen, methyl, or ethyl.
 49. 4-Oxa-5,6-didehydro-PGF1 , a compound according to claim
 48. 50. 4-Oxa-5,6-didehydro-PGF1 , a compound according to claim
 48. 51. 15-Methyl-4-oxa-5,6-didehydro-PGF1 , a compound according to claim
 48. 52. 15-Methyl-4-oxa-5,6-didehydro-PGF1 , methyl ester, a compound according to claim
 48. 53. An optically active compound of the formula:
 54. A racemic compound according to claim
 53. 55. An optically active compound according to claim
 53. 56. A compound according to claim 55 wherein CnH2n is straight chain alkylene of one to 5 carbon atoms, inclusive.
 57. A compound according to claim 56 wherein CpH2p is trimethylene.
 58. A compound according to claim 57 wherein R5 and R6 are hydrogen or methyl, being the same or different.
 59. A compound according to claim 58 wherein R5 and R6 are hydrogen.
 60. A compound according to claim 59 wherein R2 is pentyl.
 61. A compund according to claim 60 wherein Q is
 62. A compound according to claim 60 wherein Q is
 63. A compound according to claim 62 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, including the pharmacologically acceptable salts thereof when R1 is hydrogen.
 64. A compound according to claim 63 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive.
 65. A compound according To claim 64 wherein R1 is hydrogen, methyl, or ethyl.
 66. 4-Oxa-13,14-dihydro-PGF1 , a compound according to claim
 65. 67. 4-Oxa-13,14-dihydro-PGF1 , methyl ester, a compound according to claim
 65. 68. 15-Methyl-4-oxa-13,14-dihydro-PGF1 , a compound according to claim
 65. 69. 15-Methyl-4-oxa-13,14-dihydro-PGF1 , methyl ester, a compound according to claim
 65. 70. An optically active compound of the formula: 